Combining philosophical and literary perspectives, this paper argues that Mary Shelley's Frankenstein is informed by a skeptical problematic that may be traced back to the work of the young David Hume. As the foundational text on romantic monstrosity, Frankenstein has been studied from various critical angles, including that of Humean skepticism by Sarah Tindal Kareem (Eighteenth-century fiction and the reinvention of wonder. Oxford University Press, Oxford, 2014) and Monique Morgan (Romant Net 44, doi:10.7202/ 013998ar, 2006). However, the striking connections with Hume's Treatise have not been fully explored. The paper begins by comparing the three narrators of Frankenstein with three figures appearing in Hume's Conclusion to Book I: the anatomist, the explorer, and the monster. It proceeds by looking at the hybrid "anatomies" offered by Hume and Shelley, suggesting that Frankenstein might be regarded as a tragic re-enactment and radicalization of Hume's skeptical impasse. Whereas Hume alerted his readers to the dangers of a thoroughgoing skepticism only to steer his argument in a new direction, Shelley shows those dangers realized in the "catastrophe" of the Monster's birth. While Hume had called attention to the impossibility of conducting strictly scientific experiments on "moral subjects", Shelley devises a counterfactual plot and a multi-layered narrative structure in order to explore that very impossibility. Interpreting Frankenstein as an instance of the "skeptical gothic", I suggest that both the monster and the scientist (Victor) share some traits with Hume's radically skeptical philosopher, including a tendency to give up responsibility for what Stanley Cavell (The Claim of Reason: Wittgenstein, skepticism, morality, and tragedy. Oxford University Press, Oxford, 1979) called "the maintenance of shared forms of life". Relying on the work of Cavell, this paper argues that skepticism in Frankenstein is manifested as tragedy, traceable in Shelley's reliance on tragic tropes throughout the novel.